1. Field of Invention
The present invention relates to a novel reactive organic acid derivative which can be very effectively used in preparation of .beta.-lactam antibiotics. Specifically, the present invention relates to a novel reactive thiophosphate derivative of thia(dia)zole acetic acid represented by the following general formula (I): ##STR2## in which R.sup.1 represents hydrogen or an amino-protecting group;
R.sup.2 represents hydrogen C.sub.1 -C.sub.4 alkyl, or --C(R.sup.a)(R.sup.b)CO.sub.2 R.sup.c, wherein R.sup.a and R.sup.b are identical or different from each other and represent hydrogen or C.sub.1 -C.sub.4 alkyl, or R.sup.a and R.sup.b together with a carbon atom to which they are bound form a C.sub.3 -C.sub.7 cycloalkyl group, and R.sup.c is hydrogen or a carboxy-protecting group; PA1 R.sup.3 represents C.sub.1 -C.sub.4 alkyl or phenyl, or R.sup.3 together with an oxygen atom and a phosphorus atom to which it is bound form a 5- or 6-membered heterocyclic ring; and PA1 Q represents N or CH. PA1 R.sup.2 represents hydrogen, C.sub.1 -C.sub.4 alkyl, or --C(R.sup.a)(R.sup.b)CO.sub.2 R.sup.c, wherein R.sup.a and R.sup.b are identical or different from each other and represent hydrogen or C.sub.1 -C.sub.4 alkyl, or R.sup.a and R.sup.b together with a carbon atom to which they are bound form a C.sub.3 -C.sub.7 cycloalkyl group, and R.sup.c is hydrogen or a carboxy-protecting group; PA1 R.sup.3 represents C.sub.1 -C.sub.4 alkyl or phenyl, or R.sup.3 together with an oxygen atom and a phosphorus atom to which it is bound can form a 5- or 6-membered heterocyclic ring; and PA1 Q represents N or CH.
The present invention also relates to a process for preparation of the reactive derivative of formula (I), as defined above.
2. Background Art
Numerous methods for preparation of .beta.-lactam antibiotics have been disclosed in early published references and patent specifications. However, such prior methods prepare the .beta.-lactam antibiotic compound commonly starting from an organic acid having the following general formula (II) by converting it into its reactive derivative which is then subjected to an acylation reaction with an amino group of the .beta.-lactam nucleus. ##STR3## In the above formula (II), R.sup.1, R.sup.2 and Q are defined as previously described.
The reactive derivative of the compound of formula (II) which has been conventionally used in the above-mentioned prior methods includes an acid chloride, a reactive ester, a reactive amide, a mixed acid anhydride and the like. However, such reactive derivatives have some disadvantages as mentioned below. Specifically, the reactive derivative in the form of an acid chloride or a mixed acid anhydride should be prepared under stringent reaction conditions and further is unstable, so that it might be used in situ for the acylation reaction without isolation. This may be the major reason for the formation of by-products. Furthermore, when the reactive derivative of the compound of formula (II) is in the form of a reactive ester and a reactive amide, it has also disadvantages in that both the yield and the reactivity of such reactive derivatives are very low and the acylation reaction requires a long reaction time due to their low reactivity and, further, the reaction by-products, for example, a hydroxy derivative such as 1-hydroxybenzotriazole and a thiol derivative such as 2-mercaptobenzothiazole, can be hardly removed.
In addition, Japanese Laid-open Patent Publication No. (Sho) 57-175196, pages 891-892, discloses diphenyloxophosphoryl (Z)-(2-aminothiazol-4-yl)methoxyimino acetate of formula (A), which can be prepared from (Z)-(2-aminothiazol-4-yl)methoxyimino acetic acid and a diphenyl chlorophosphate derivative. ##STR4##
However, the compound of formula (A) is an unstable reactive mixed acid anhydride, which cannot be isolated, and therefore can affect adversely the reaction in the next step.
Accordingly, the present inventors have continuously studied to discover a method which can solve the problems involved in the known reactive derivatives as previously described. As a result, we have discover that a novel reactive derivative having a suitable reactivity and stability can be prepared from the organic acid of formula (II) above and a chlorothiophosphate derivative substantially in a convenient manner and in a high yield and then completed the present invention.
Therefore, it is an object of the present invention to provide a novel reactive thiophosphate derivative of thia(dia)zole acetic acid of formula (I), as defined above, which can be very effectively used for preparation of the .beta.-lactam antibiotic compound.
It is a further object of this invention to provide a process for preparing the novel reactive derivative of formula (I).
The foregoing has outlined some of the more pertinent objects of the present invention. These objects should be construed to be merely illustrative of some of the more pertinent features and applications of the invention. Many other beneficial results can be obtained by applying the disclosed invention in a different manner or modifying the invention within the scope of the disclosure. Accordingly, other objects and a more thorough understanding of the invention may be had by referring to the disclosure of invention, in addition to the scope of the invention defined by the claims.